Renal alterations in Pou3f3L423P mutant mice

Rieger, Alexandra (2018): Renal alterations in Pou3f3L423P mutant mice. Dissertation, LMU München: Tierärztliche Fakultät

Abstract

Mammalian nephrogenesis is a complex process that involves the precise timely and spatially coordinated interaction of a plethora of signaling molecules. During terminal nephron segmentation, POU3F3 (aka BRN1), a POU domain class 3 transcription factor, plays a critical role in the differentiation of the distal tubule, in particular the thick ascending limb of the loop of Henle (TAL). In knock-out mice, deficiency of POU3F3 leads to underdevelopment of the TAL, lack of differentiation of TAL and macula densa cells, and perinatal death due to renal failure. Pou3f3L423P mutant mice were established in the phenotype-driven Munich ENU Mouse Mutagenesis Project within a special screen for increased plasma urea levels to detect novel mouse models for kidney diseases. These mice carry a recessive point mutation in the highly conserved homeodomain of POU3F3. In contrast to Pou3f3 knock-out mice, homozygous Pou3f3L423P mutants are viable and fertile. The present study used functional, as well as qualitative and quantitative morphological analyses to characterize the renal phenotype of juvenile (12 days) and aged (60 weeks) homo- and heterozygous Pou3f3L423P mutant mice and age-matched wildtype littermates of both sexes. In both age groups, homozygous mutants vs. control mice displayed significantly smaller kidney volumes, decreased nephron numbers and smaller mean glomerular volumes. Besides, the absolute TAL volumes and the volume densities of TAL in the kidney were significantly reduced in Pou3f3L423P mutants. There were no histologically or ultrastructurally detectable lesions of TAL or glomerular cells. Aged homozygous mutants displayed increased serum urea concentrations and reduced specific urine gravity, but no evidence of glomerular dysfunction. These results confirm the important function of POU3F3 during nephron patterning, especially in development of the TAL. Furthermore they provide strong evidence that POU3F3 is also involved in the regulation of nephron induction, nephron endowment, and nephron size in the murine kidney, while the mutation is not associated with a distinct pattern of morphological glomerular lesions. The detailed characterization of the renal morphology of Pou3f3L423P mutants provided the basis for further analyses of POU3F3 actions, and showed that Pou3f3L423P mutant mice represent a valuable research model for nephrological studies examining the role of congenital low nephron numbers in kidney disease development and progression.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 590 Tiere (Zoologie)
• Fakultäten: Tierärztliche Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 27. Juli 2018
• 1. Bericht­erstatter:in: Wanke, Rüdiger